In view of the known biochemical mechanism of folic acid coenzyme systems, the homeosteric replacements of one of the nitrogen atom in the pyrazine moiety by oxygen should produce effective antimetabolites; i.e., derivatives possessing the pyrimido (4,5-b)(1,4)oxazine and the pyrimido (5,4-b)(1,4)oxazine ring systems. The synthesis of such analogs of the vitamin will permit a study of the molecular binding in the various enzymic systems associated with the coenzyme structures. Further, the pyrimido (5,4-b)(1,4)oxazine nucleus does not have an N-5 position for single carbon transfer reactions and may thus be of potential interest as a chemotherapeutic agent. At the molecular level, it is the pyrazine moiety which is directly involved in covalent reactions with single carbon units which ultimately permits the various enzymic reactions of the molecule.